In recent years much attention has been directed toward the development of radiopharmaceuticals that will concentrate in tumor tissue and permit external imaging of the tumor. Such an approach, if completely successful, would have obvious advantages over other methods currently employed for staging and followup of patients with malignant disease because of the inherent simplicity, lower cost, and low morbidity of scanning techniques. Although an ideal tumor imaging agent has not yet come into routine clinical use, the chance observation that the radionuclide gallium--7 citrate accumulated in soft tissue tumors has led to extensive clinical experience with this particular tumor scanning agent.
Another more rational approach to tumor imaging is to label tumor-specific drugs or antibodies which might selectively concentrate in tumors. The anti-tumor antibiotic bleomycin is such a drug and it has been shown to concentrate in skin, lung, and certain tumors. It has recently been approved for general use on the basis of its demonstrated clinical effectiveness against squamous cell carcimomas, lymphoma, and testicular tumors.
Bleomycin has the desirable characteristic of chelation with a number of bivalent and trivalent cations, such as cobalt, lead, indium and copper. It has thus been possible to chelate radioactive isotopes of such metals to bleomycin and thereby produce radioactive agents which can be used to detect and visualize tumors.
Bleomycin is a mixture of glycopeptide antibiotics discovered by Umezawa et al, in 1962, and isolated from the cultured broth of Streptomyces verticillus. It is effective against various animal and human tumors such as squamous cell carcinomas, malignant lymphomas, and testicular tumors. The antibiotic also inhibits the growth of gram positive and gram negative bacteria and appears to bind to cellular DNA.
Thirteen distinct, but closely related, bleomycin peptides have been isolated. They are relatively high molecular weight (ca. 1200), and are known to form metal chelates, as well as being concentrated in tumors.
Bleomycin can be loosely chelated with a wide variety of radionuclides including indium 111, cobalt 57 and lead 203. Studies have been conducted of .sup.111 In-labeled bleomycin as a tumor-imaging agent in patients with a wide variety of neoplasms. The precise mechanism of tumor labeling with .sup.111 In-bleomycin is not fully understood. Although .sup.111 In alone will localize tumors to some extent, the results indicate that tumor localization occurs more frequently with .sup.111 In-labeled bleomycin. However, the radionuclide (.sup.111 In) can dissociate from bleomycin; serum transferrin and the erythroid compartment of the bone marrow both compete with bleomycin for 111In binding. Ionic indium released by bleomycin on dissociation is bound virtually quantitatively to transferrin and accumulated by bone marrow erythroid precursor cells.
A broad spectrum of tumors can be localized with radioactive-labeled bleomycin, despite the lack of therapeutic efficacy of bleomycin alone against these tumors. It appears that two essential steps are involved at the cellular level for bleomycin to exert its oncolytic effect: (a) selective uptake by tumor cells and (b) specific inhibition of DNA synthesis and cell death due to bleomycin's antibiotic effect. Thus, bleomycin can serve as a vehicle for delivering local radioactivity to the target tumor tissue.
.sup.111 In-bloemycin is an important tumor-scanning agent, but it has certain disadvantages. For instance, bleomycin is known to concentrate in the lung and it is possible that diffuse pulmonary uptake of .sup.111 In-bleomycin identifies either those patients with pulmonary damage or those who are susceptible to subsequent development of bleomycin pulmonary toxicity. Another disadvantage is that the .sup.111 In-bleomycin dissociates in body fluids and releases .sup.111 In ions which are absorbed by normal liver and bone marrow which are thereby imaged. Apparently .sup.111 In dissociated from .sup.111 In-bleomycin competes with iron for binding to transferrin and for incorporation into erythroid precursors in the bone marrow.
A tumor-imaging agent should have the following properties: (a) it should be taken up by all malignant tissue in the patient (i.e., highly sensitive); (b) it should not be taken up by any normal or nonmalignant tissues (i.e., highly specific); (c) it should be safe to administer and not give an excessive radiation dose (so that it may be easily and safely employed for serial evaluations); and (d) it should be capable of providing good images with currently available instrumentation (so that only the intrinsic resolution of the instrument would limit the size of the minimally detectable lesion). While clinical data indicate that .sup.111 In-bleomycin is a safe and clinically useful tumor-imaging agent, it is not ideal by these criteria, although it does represent an advance in efforts to develop the ideal radiopharmaceutical.
Lesion detectability is dependent upon two factors: (a) absolute uptake of the agent in question by the tumor and (b) the contrast between the activity present in the tumor and that in adjacent normal tissues. While .sup.111 In-bleomycin is effective in certain areas, there is still need for radioactive scanning agents which are more stable then chelated materials such as .sup.111 In-bleomycin and which are more selective in tissue uptake.